A complication of seemingly successful ophthalmic surgical procedures is a gradual or a sudden impairment of vision. This complication is commonly reported in patients after cataract removal, although it has been observed after surgical procedures such as scleral buckles, and is generally believed to be due to vascular incompetence, vitrous traction and inflammation of the vascular region of the eye. The same type of vision impairment has been observed in patients who have undergone a subsequent artificial lens implantation as well; however, incidence appears to be slightly lower in the pseudophakic patients when compared with aphakic patients. S. Severin, American Journal of Ophthalmology, 90:223-225, 1980.
Approximately five percent of cataract patients demonstrate these symptoms. The onset of this disease, commonly termed cystoid macular edema, most frequently occurs from four to sixteen weeks after cataract extraction. However, vision loss has been reported to manifest itself as long as thirteen years after cataract extraction. The diagnosis of cystoid macular edema is most frequently confirmed with a fluorescein angiogram which detects leaking of fluorescein from the optic disk and the macular capillaries as well as other retinal capillaries.
Approximately 70 percent of the patients suffering these complications after surgery recover spontaneously but recovery may take up to one year. The remaining group continues to suffer chronic vision loss.
There have been various attempts to resolve or to prevent this vision loss including topical administration of indomethacin, topical administration of corticosteroids, topical administration of combinations of indomethacin and corticosteroids, oral administration of indomethancin, oral administration of corticosteriods, implantation of an ultraviolet chromophore, and injection of betamethasone.
Indomethacin treatment has met with mixed results, however.
Yannuzzi et al, Ophthalmology, 88:9:947-953, 1983, conducted a study using a pretreatment of topical administration of 1 percent aqueous indomethacin to reduce the incidence of aphakic cystoid macular edema (ACME) after acknowledging that oral administration of indomethacin had been ineffective, in part due to the high incidence of gastrointestinal and central nervous system side effects. Their study indicated that the short term effects of topical indomethacin pretreatment were positive, reducing the incidence of ACME, but that by 12 to 18 months after surgery, the effect was insignificant. Furthermore, Yannuzzi et al concluded that there was no evidence that the most critical aspect to visual rehabilitation of the macula, central vision, benefited from prophylactic indomethacin pretreatment.
Miyake et al studied the topical administration of indomethacin in the prevention of cystoid macular edema after retinal detachment surgery. Their study found some early postoperative efficacy of the treatment but could not establish long term effects, i.e., greater than twelve weeks after surgery. K. Miyake, et al American Journal of Ophthalmology, 95:451-456, 1983.
Jampol has reported other unsuccessful attempts at topical indomethacin treatment. He also reported that combinations of topical indomethacin with topical corticosterioids had questionable short term results and a high rate of relapse. L. Jampol, Ophthalmology, 92:6:807-810, June, 1985.
The results of oral indomethacin administration studies have been equally as inconclusive. Postoperative, but presymptomatic treatment with indomethacin has resulted in a short term lower incidence, but not in an elimination of aphakic cystoid macular edema. However, long term effects could not be determined because of poor patient compliance due to the undesirable side effects of the medication including gastrointestinal irritation and neurological symptoms. R. Klein, et al. American Journal of Ophthalmology 87:487-489, 1979.
Jampol has also suggested the use of indomethacin and other non-steroids for the prophylaxis of aphakic cystoid macular edema and the use of corticosteroids for temporary beneficial therapeutic effects with respect to cystoid macular edema. However, the side effects of both indomethacin and corticosteroids make such treatment impractical. As an alternative treatment, Jampol has additionally suggested the placement of an ultraviolet radiation absorbing chromophore in a posterior chamber intraocular lens implant. L. Jampol, Archives of Ophthalmology, 103:1134-1135, August 1985.
Other experimental methods of treatment have comprised the injection of betamethasone directly into the subtendon space and the oral administration of indomethacin after the diagnosis of cystoid macular edema has been confirmed by fluorescein angiography. This did not result in success in a study conducted at the University of California, San Francisco, but topical corticosteroid treatment was suspected to have contributed to vision improvement. The resolution of vision could not be directly related to the topical corticosteroid treatment, however. S. Severin, American Journal of Ophthalmology, 90:223-225, 1980. See also, D. Jacobson et al, American Journal of Ophthalmology, 77:4:445-447, April 1974.
Witzel et al, U.S. Pat. No. 4,720,503, disclose the use of N-substituted fused-heterocyclic carboxamide derivatives to inhibit both cyclooxygenase and lipoxygenase production in the topical treatment of eye inflammation. However, Witzel et al explain that while cyclooxygenase inhibitors alone, such as diflunisal, inhibit only the process wherein arachidonic acid is oxygenated via cyclooxygenase to prostaglandins and thromboxanes, 5-lipoxygenase inhibitors are linked to the treatment of eye inflammation.
A treatment for the loss of vision induced by ophthalmic surgery and particularly induced by cystoid macular edema has been elusive for well over the last fifteen years.
Diflunisal is a prostaglandin synthetase inhibitor that has proven useful in the treatment of various inflammatory disease of the skelato-muscular system.
Ruyle et al, U.S. Pat. Nos. 3,681,445, 3,714,226, and 4,044,049, disclose oral administration of diflunisal in the treatment of inflammatory diseases, particularly rheumatoid arthritis, osteoarthritis, gout, infectious arthritis and rheumatic fever. However, diflusinal has been contradicted for treatment of the eye. Adverse eye findings have been reported with agents in the class of diflunisal, and peripheral edema has been observed in patients being treated with diflunisal. (Physician's Desk Reference, 43rd Edition, Medical Economics Company, Inc., 1989).
Sunshine et al, U.S. Pat. No. 4,749,721, disclose the use of diflunisal in combination with other active ingredient(s) for the relief of cough, cold and coldlike symptoms.
Dorn, U.S. Pat. No. 4,542,158, discloses the use of esters of diflunisal as anti-inflammatories with low irritancy of the mucous membranes particularly in the treatment of rheumatoid arthritis, osteoarthritis, gout, infectious arthritis, and rheumatic fever. Dorn also discloses that the esters can be contained in a cream, ointment, jelly, solution or suspension for topical application.
A novel method of use of diflunisal has now been discovered which results in the prevention or improvement of vision loss which typically occurs after ophthalmic surgery. In the present invention, diflunisal is administered to a subject either preoperatively, preoperatively and postoperatively but presymptomatically, postoperatively but presymptomatically, or postsymptomatically in correspondingly prophylactically effective amounts or therapeutically effective amounts sufficient to prevent the loss of visual acuity or to improve the visual acuity of the subject.
It is a further object of the invention to provide a topical dosage unit of diflunisal, particularly for use in the above method.